title: Simvastatin treatment highlights a new role for the isoprenoid/cholesterol biosynthetic pathway in the modulation of emotional reactivity and cognitive performance in rats.
abstract: The aim of the present work was to shed light on the role played by the isoprenoid/cholesterol biosynthetic pathway in the modulation of emotional reactivity and memory consolidation in rodents through the inhibition of the key and rate-limiting enzyme 3-hydroxy 3-methylglutaryl Coenzyme A reductase (HMGR) both in vivo and in vitro with simvastatin. Three-month-old male Wistar rats treated for 21 days with simvastatin or vehicle were tested in the social interaction, elevated plus-maze, and inhibitory avoidance tasks; after behavioral testing, the amygdala, hippocampus, prefrontal cortex, dorsal, and ventral striatum were dissected out for biochemical assays. In order to delve deeper into the molecular mechanisms underlying the observed effects, primary rat hippocampal neurons were used. Our results show that HMGR inhibition by simvastatin induces anxiogenic-like effects in the social interaction but not in the elevated plus-maze test, and improves memory consolidation in the inhibitory avoidance task. These effects are accompanied by imbalances in the activity of specific prenylated proteins, Rab3 and RhoA, involved in neurotransmitter release, and synaptic plasticity, respectively. Taken together, the present findings indicate that the isoprenoid/cholesterol biosynthetic pathway is critically involved in the physiological modulation of both emotional and cognitive processes in rodents.
authors.affiliation: Department of Science, University Roma Tre, Viale Marconi, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Segatto
authors.affiliation: Department of Science, University Roma Tre, Viale Marconi, Rome, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Manduca
authors.affiliation: Department of Science, University Roma Tre, Viale Marconi, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Lecis
authors.affiliation: Department of Science, University Roma Tre, Viale Marconi, Rome, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Rosso
authors.affiliation: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Jozwiak
authors.affiliation: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Swiezewska
authors.affiliation: Department of Science, University Roma Tre, Viale Marconi, Rome, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Department of Science, University Roma Tre, Viale Marconi, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Trezza
authors.affiliation: Department of Science, University Roma Tre, Viale Marconi, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pallottini
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D050882:CREB-Binding Protein / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects*; D000076122:Disks Large Homolog 4 Protein; D004644:Emotions / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D013729:Terpenes; D014280:Triglycerides; D002784:Cholesterol; D019821:Simvastatin; D050882:CREB-Binding Protein